title: Putting the Rit in cellular resistance: Rit, p38 MAPK and oxidative stress.
abstract: Cells mobilize diverse signaling pathways to protect against stress-mediated injury. Ras family GTPases play critical roles in this process, controlling the activation and integration of multiple regulatory cascades. p38 mitogen-activated protein kinase (MAPK) signaling serves as a critical fulcrum in this process, regulating networks that stimulate cellular apoptosis but also promote cell survival. However, this functional dichotomy is incompletely understood, particularly regulation of p38-dependent survival. Here, we discuss our recent evidence that the Rit GTPase associates with and is required for stress-mediated activation of a scaffolded p38-MK2-HSP27-Akt pro-survival signaling cascade. Drosophila lacking D-Ric, a Rit homologue, are susceptible to a variety of environmental stresses, while embryonic fibroblasts derived from Rit knockout mice display blunted stress-dependent signaling and decreased viability. Conversely, expression of constitutively active Rit triggers p38-Akt-dependent cell survival. Together, our studies establish Rit as the central regulator of an evolutionarily conserved, p38-dependent signaling cascade that functions as a critical survival mechanism in response to stress.
authors.affiliation: Department of Molecular and Cellular Biochemistry; College of Medicine; University of Kentucky; Lexington, KY USA.
authors.forename: Weikang
authors.initials: W
authors.lastname: Cai
authors.forename: Geng-Xian
authors.initials: GX
authors.lastname: Shi
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Andres
keywords: Akt; GTPases; HSP27; MAPK; ROS; Ras; cell survival; stress